Method and Apparatus for Application of a Neural Stimulus

ABSTRACT

A method of applying a neural stimulus with an implanted electrode array involves applying a sequence of stimuli configured to yield a therapeutic effect while suppressing psychophysical side effects. The stimuli sequence is configured such that a first stimulus recruits a portion of the fibre population, and a second stimulus is delivered within the refractory period following the first stimulus and the second stimulus being configured to recruit a further portion of the fibre population. Using an electrode array and suitable relative timing of the stimuli, ascending or descending volleys of evoked responses can be selectively synchronised or desynchronised to give directional control over responses evoked.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/117,586, filed on Nov. 13, 2013, which is a U.S. National StageApplication under 35 U.S.C. §371 of International Application No.PCT/AU2012/000515, filed on May 11, 2012, which claims priority toAustralian Provisional Patent Application No. AU2011901828 filed May 13,2011 and Australian Provisional Patent Application No. AU2011901829filed May 13, 2011, all of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to application of a neural stimulus, andin particular relates to applying a neural stimulus in a controlledmanner by using one or more electrodes implanted proximal to the neuralpathway.

BACKGROUND OF THE INVENTION

There are a range of situations in which it is desirable to apply neuralstimuli in order to give rise to a compound action potential (CAP). Forexample, neuromodulation is used to treat a variety of disordersincluding chronic pain, Parkinson's disease, and migraine. Aneuromodulation system applies an electrical pulse to tissue in order togenerate a therapeutic effect. When used to relieve chronic pain, theelectrical pulse is applied to the dorsal column (DC) of the spinalcord. Such a system typically comprises an implanted electrical pulsegenerator, and a power source such as a battery that may be rechargeableby transcutaneous inductive transfer. An electrode array is connected tothe pulse generator, and is positioned in the dorsal epidural spaceabove the dorsal column. An electrical pulse applied to the dorsalcolumn by an electrode causes the depolarisation of neurons, andgeneration of propagating action potentials. The fibres being stimulatedin this way inhibit the transmission of pain from that segment in thespinal cord to the brain. To sustain the pain relief effects, stimuliare applied substantially continuously, for example at 100 Hz.

While the clinical effect of spinal cord stimulation (SCS) is wellestablished, the precise mechanisms involved are poorly understood. TheDC is the target of the electrical stimulation, as it contains theafferent Aβ fibres of interest. Aβ fibres mediate sensations of touch,vibration and pressure from the skin, and are thickly myelinatedmechanoreceptors that respond to non-noxious stimuli. The prevailingview is that SCS stimulates only a small number of Aβ fibres in the DC.The pain relief mechanisms of SCS are thought to include evokedantidromic activity of Aβ fibres having an inhibitory effect, and evokedorthodromic activity of Aβ fibres playing a role in pain suppression. Itis also thought that SCS recruits Aβ nerve fibres primarily in the DC,with antidromic propagation of the evoked response from the DC into thedorsal horn thought to synapse to wide dynamic range neurons in aninhibitory manner.

Neuromodulation may also be used to stimulate efferent fibres, forexample to induce motor functions. In general, the electrical stimulusgenerated in a neuromodulation system triggers a neural action potentialwhich then has either an inhibitory or excitatory effect. Inhibitoryeffects can be used to modulate an undesired process such as thetransmission of pain, or to cause a desired effect such as thecontraction of a muscle.

The action potentials generated among a large number of fibres sum toform a compound action potential (CAP). The CAP is the sum of responsesfrom a large number of single fibre action potentials. The CAP recordedis the result of a large number of different fibres depolarising. Thepropagation velocity is determined largely by the fibre diameter and forlarge myelinated fibres as found in the dorsal root entry zone (DREZ)and nearby dorsal column the velocity can be over 60 ms⁻¹. The CAPgenerated from the firing of a group of similar fibres is measured as apositive peak potential P1, then a negative peak N1, followed by asecond positive peak P2. This is caused by the region of activationpassing the recording electrode as the action potentials propagate alongthe individual fibres. An observed CAP signal will typically have amaximum amplitude in the range of microvolts, whereas a stimulus appliedto evoke the CAP is typically several volts.

For effective and comfortable operation, it is necessary to maintainstimuli amplitude or delivered charge above a recruitment threshold,below which a stimulus will fail to recruit any neural response. It isalso necessary to apply stimuli which are below a comfort threshold,above which uncomfortable or painful percepts arise due to increasingrecruitment of Ai fibres which are thinly myelinated sensory nervefibres associated with acute pain, cold and pressure sensation. Inalmost all neuromodulation applications, a single class of fibreresponse is desired, but the stimulus waveforms employed can recruitother classes of fibres which cause unwanted side effects, such asmuscle contraction if motor fibres are recruited. The task ofmaintaining appropriate neural recruitment is made more difficult byelectrode migration and/or postural changes of the implant recipient,either of which can significantly alter the neural recruitment arisingfrom a given stimulus, depending on whether the stimulus is appliedbefore or after the change in electrode position or user posture.Postural changes alone can cause a comfortable and effective stimulusregime to become either ineffectual or painful.

Any discussion of documents, acts, materials, devices, articles or thelike which has been included in the present specification is solely forthe purpose of providing a context for the present invention. It is notto be taken as an admission that any or all of these matters form partof the prior art base or were common general knowledge in the fieldrelevant to the present invention as it existed before the priority dateof each claim of this application.

Throughout this specification the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

SUMMARY OF THE INVENTION

According to a first aspect the present invention provides a method ofapplying a neural stimulus with an implanted electrode array, the methodcomprising:

-   -   using the electrode array to applying a sequence of stimuli        configured to yield a therapeutic effect while suppressing        psychophysical side effects, the stimuli sequence configured        such that a first stimulus recruits a portion of the fibre        population, and a second stimulus is delivered within the        refractory period following the first stimulus and the second        stimulus being configured to recruit a further portion of the        fibre population.

According to a second aspect the present invention provides a device forapplying a neural stimulus, the device comprising:

-   -   at least one electrode configured to be positioned alongside a        neural pathway; and    -   a control unit configured to apply a sequence of neural stimuli        which are configured to yield a therapeutic effect while        suppressing psychophysical side effects, the stimuli sequence        configured such that a first stimulus recruits a portion of the        fibre population, and a second stimulus is delivered within the        refractory period following the first stimulus and the second        stimulus being configured to recruit a further portion of the        fibre population.

By providing for a second stimulus to be delivered in the neuralrefractory period following the first stimulus, the present inventionprovides for de-correlated, or less correlated, fibre responses to beevoked by such stimuli.

The sequence of neural stimuli may comprise more than two stimuli, eachbeing delivered in the refractory period following a previous stimulusin the sequence.

The sequence of neural stimuli may comprise stimuli of ascendingamplitude.

The sequence of neural stimuli may be applied sequentially by a singleelectrode.

Alternatively, the sequence of neural stimuli may be appliedsequentially by more than one electrode. In such embodiments, the secondstimulus is preferably delivered at a time after the first stimuluswhich allows for cessation of the first stimulus and allows forpropagation of a first neural response evoked by the first stimulus fromthe first electrode to the second electrode, so that the second stimulusis delivered during a refractory period of neurons proximal to thesecond electrode after activation of those neurons by the evoked neuralresponse from the first stimulus.

Additionally or alternatively, in some embodiments the sequence ofneural stimuli may be applied by consecutive electrodes positioned alongan electrode array.

In embodiments where the sequence of neural stimuli is appliedsequentially by more than one electrode, the timing of the respectivestimuli in the sequence may be controlled in order to causespatiotemporal alignment of the respective evoked responses propagatingin a first direction along the nerve fibre to thereby cause correlationand summation of evoked responses in the first direction, while causingspatiotemporal misalignment of the respective evoked responsespropagating in a second direction opposite the first direction along thenerve fibre, to thereby decorrelate evoked responses propagating in thesecond direction. Such embodiments may be advantageous in decorrelatingevoked potentials propagating toward the brain, where it is desired toavoid or minimise any percept from the stimuli.

In some embodiments of the invention, the sequence of neural stimuli maybe followed by a single stimulus which is not applied during therefractory period of any preceding stimulus, and which is not closelyfollowed by any subsequent stimulus in the refractory period of thesingle stimulus. Such embodiments may be applied in order to enable anevoked response measurement to be made following the single stimulus, toenable ongoing refinement of stimulus parameters of the sequence ofneural stimuli.

According to another aspect the present invention provides a computerprogram product comprising computer program code means to make acomputer execute a procedure for applying a neural stimulus with animplanted electrode array, the computer program product comprisingcomputer program code means for carrying out the method of the firstaspect.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the invention will now be described with reference to theaccompanying drawings, in which:

FIG. 1 illustrates an implantable device suitable for implementing thepresent invention;

FIG. 2 a shows the Aβ response amplitude growth functions forstimulation of the sheep spinal cord at 40, 80 and 120 μs, while FIG. 2b shows the compound action potential recorded at equivalent charges forthe three different pulse widths;

FIG. 3 illustrates summation of a sequence of overlapped neuralresponses;

FIG. 4 is a schematic illustration of a potential pulse sequence and theamplitude growth curve associated with the sequence;

FIG. 5 illustrates ERT responses to bursts of stimulation with differingfrequencies;

FIG. 6 illustrates a stimuli scheme to generate stimuli which result insynchronising Aβ activation in the antidromic direction and adesynchronising activity in the orthodromic direction:

FIG. 7 illustrates experimental results obtained by applying a series offour stimuli of ascending amplitude on four adjacent electrodes to asheep spinal cord;

FIG. 8 illustrates experimental results obtained in response to stimulibursts of different inter-stimulus intervals; and

FIG. 9 illustrates a suitable feedback controller for controlling theparameters of the stimuli burst in an automated manner.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 illustrates an implantable device 100 suitable for implementingthe present invention. Device 100 comprises an implanted control unit110, which controls application of a sequence of neural stimuli inaccordance with the present invention. In this embodiment the unit 110is also configured to control a measurement process for obtaining ameasurement of a neural response evoked by a single stimulus deliveredby one or more of the electrodes 122. Device 100 further comprises anelectrode array 120 consisting of a three by eight array of electrodes122, each of which may be selectively used as either the stimuluselectrode or sense electrode, or both.

The activation and simultaneous suppression of different areas of tissueis highly desired for treatment of a number of neurological disorders.The activation of micturition or defection without contraction of thesphincter is highly desirable for treatment of incontinence. The goal ofstimulation of the spinal cord is to block transmission of pain signalsfrom Aδ and C fibres, via the inhibitory effect of the activation of Aβfibres. The ascending Aβ fibres produce a psycho-physiological responsewhich results in the paraesthesia (described as tingling by recipients).A number of ways to reduce or eliminate this effect have been suggested.It has been reported that burst mode stimulation or continuousstimulation at high frequencies can produce pain relief withoutaccompanying paraesthesia, however the mechanisms are not clear.

One possible explanation is that the high frequency stimulation resultsin a highly uncorrelated neural firing pattern in the ascending Aβtracts. High frequency stimulation results in the continuous activationof the fibres and produces a randomised firing pattern. The recoverytime (refractory period) between each fibre is slightly different and ifa depolarisation potential is present as the fibre comes out ofrefractory period, it will depolarise again, but not synchronised withother fibres which may still be in their refractory periods. The netresult is a randomisation of the firing pattern and a return of thestochastic response in the fibre.

Measurements of the evoked neural response provide a direct measure ofthe degree of correlation of the firing pattern. FIG. 2 a shows the Aβresponse amplitude growth functions with respect to stimulus amplitude,for stimulation of the sheep spinal cord at 40, 80 and 120 μs. Therecruitment is related to charge and so stimulation at 1 mA for 120 μsproduces an equivalent charge for stimulation at 3 mA for 40 μs, withvertical lines highlighting two respective points of equal chargedelivery for each trace. FIG. 2 b shows the compound action potentialrecorded at equivalent charges for the three different pulse widths. Thepeak height is smaller and the evoked response peak is wider at theequivalent charge for the longer pulse width than for the shorter pulsewidth, and this is indicative of a less correlated evoked response.

The probability of any single fibre responding is a function of theproperties and history of the fibre and the amplitude of the currentpulse. Although short and long pulses for an equivalent charge mayrecruit the same number of fibres the longer lower current amplitudepulse will recruit the fibres over a longer time scale than the highercurrent shorter pulse width.

Patients report a preference for stimulation with longer pulse widthsand the reason for this preference may be because the perceptual sideeffect is lower, because there is a lower correlation between the fibresfiring. Given this observation, highly uncorrelated responses may giverise to much lower psycho-physical side effects such as tinglingsensations and paraesthesia. The evoked responses measured for thelonger pulse widths are broader in FIG. 2 b, indicating less correlationin the firing pattern.

Measurement of the evoked response provides a unique way to assess thedegree of correlation amongst fibres in a group, as the peak width andamplitude of the measured response directly relates to the degree oftiming synchronisation of the single fibre action potentials which sumto form the compound action potential. The goal of stimulus design is toachieve a high level of recruitment at the segmental level and a lowlevel of correlation for the ascending segments. The neural responsemeasurement obtained at each sense electrode may be conducted inaccordance with the techniques set out in Daly (2007/0225767), thecontent of which is incorporated herein by reference. Additionally oralternatively, the neural response measurement may be conducted inaccordance with the techniques set out in Nygard (U.S. Pat. No.5,785,651), the content of which is incorporated herein by reference.Additionally or alliteratively, the neural response measurement may beconducted in accordance with the techniques set out in the Australianprovisional patent application filed simultaneously herewith in the nameof National ICT Australia Ltd entitled “Method and apparatus formeasurement of neural response”.

The degree of correlation within an evoked response can be measured withsuch techniques, and pulse sequences can be designed to produce evokedresponses of a desired character. A typical recruitment curve is shownin FIG. 2 a. The strength of the Aβ potentials directly relates to thenumber of fibres recruited, and therefore stimulation at successivelarger and larger pulse amplitudes will recruit successively morefibres. If the pulses are timed so that they occur within the refractoryperiod of the excited neurons from the previous pulse then different subpopulations of neurons can be selected with each pulse.

The timing of each pulse can be so arranged so that the travelling CAPsfrom each individual pulse cancel each other as they sum at somedistance from the stimulation site. This indicates the degree ofdesynchronisation between the fibres, and as the sensory input is basedon correlation of firing patterns the sensation (paraesthesia) isreduced. However, the activation of the inhibitory effect of the Aβfibres at the segmental level is not reduced, permitting Aβ inhibitionof Ai and C propagation to occur, as desired.

FIG. 3 illustrates the principle of applying a sequence of neuralstimuli and allowing the respective evoked responses 302, 304, 306 topropagate along the fibre. The numerical summation of five suchpartially overlapping compound action potentials, of which only threeappear in FIG. 3, is shown at 308. FIG. 3 shows the effect of thesummation of the evoked response from five pulses with the timingintervals between the pulses so arranged as result in the arrival of theevoked response waveform at a designated point along the electrode arraysuch that the averaged signal recorded at that point is minimised. Forthe data shown in FIG. 3 the timing difference between each cathodicpulse is 0.3 ms.

FIG. 4 is a schematic illustration of a potential pulse sequence (lower)and the amplitude growth curve associated with the sequence (upper).Current levels A-C are represented on both portions of FIG. 4. Theinitial pulse of amplitude A can be expected to recruit only a portionof the available population. Application of the subsequent stimulus ofgreater amplitude can then be expected to recruit a further portion, butnot all, of the available neural population, even though stimulus B isapplied during the refractory period after stimulus A. Similarly,stimulus C can be expected to recruit a further portion of the availableneural population. C may be applied during the refractory period ofstimulus B only, or possibly within the refractory period of bothstimuli A and B. The sequence of neural stimuli A-B-C can thus beexpected to recruit perhaps a similar amount of the available neuralpopulation as would stimulus C if applied alone, however the progressiverecruitment of portions of the neural population at progressive timesprovides for a significantly decorrelated evoked response as compared tothe response resulting from a single stimulus of amplitude C.

The concept of a selection of stimulus sequences based on the ERTrecorded parameters can be greatly extended. For instance the example ofFIG. 4 demonstrates achieving an uncorrelated ensemble response in thefibre population being stimulated.

FIG. 5 illustrates ERT responses to bursts of stimulation with differingfrequencies. The degree of correlation can be inferred from the ERTsignal. A normal stimulus can be used to assess the stimulation responseamplitude in the absence of any further desynchronising pulses. Theamplitude of the single probe pulse is adjusted to represent the totalcharge delivered over time for the corresponding desynchronising pulsetrain. The amplitude of the response measured from the single probepulse represents a fully synchronised response. The desynchronisingpulse train is then output and the response measured. The ratio of thetwo responses is proportional to the level of synchronisation and so canbe used as a control parameter for adjusting the characteristics of thedevice. For instance the control parameter may be adjustable by thepatient to allow the patient to adjust the level of perceivedparaesthesia. The control variable may also be used by the system fordetection of a change of state in the neural tissue for a diagnosticpurpose.

A single non-decorrelating stimulus can be applied to the nerve by thedevice periodically or occasionally in order to elicit an evokedresponse which is then used as the input to the control loop. This probestimulus can be adjusted so that its charge is equivalent to the chargepresented by the desynchronising stimuli. The frequency of the probepulse to desynchronising pulses can then be adjusted to minimise theperceptual side effects. The probe frequency can also be adjusted ondemand, responding more rapidly to changes in movement, for example.

Conduction of the compound action potentials occurs both orthodromically(up the spine) and antidromically (down the spine). Careful choice ofstimulus design can be used to create a situation where the degree ofsynchronisation can be different in both directions, and controllablyso. For example it may be desirable to generate stimuli which result insynchronising Aβ activation in the antidromic direction and adesynchronising activity in the orthodromic direction. One possiblescheme for doing this is illustrated in FIG. 6. A stimulus pulse,preferably biphasic, is discharged at an electrode (electrode ‘0’indicated on the left side of FIG. 6). At some time interval later a2^(nd) stimulus pulse is discharged between another two electrodes. Forconvenience this is illustrated in FIG. 6 as the electrode (number “1”)adjacent to the first electrode. The 2^(nd) discharge is arranged sothat it occurs in time and place such that its resultant CAP propagationto an electrode (e.g. ‘+6’) in one direction (the upward direction inFIG. 6) sums with each other evoked CAP. In contrast, in the otherdirection (the downward direction in FIG. 6), the respective CAPs aremisaligned and decorrelated for example when observed at electrode ‘−3’.

A possible means but not the only means to achieve such directionalselectivity of CAP correlation is to arrange a series of stimulus pulseswith an interpulse interval equal to the difference in propagation timerequired for desynchronisation of the CAP in the ascending direction.

Note that the order in which the stimuli are presented does not need tobe sequential. The amplitudes of the individual stimuli can also bevaried according to the scheme of FIG. 4. The timing of presentation canalso be dithered to adjust the timing.

FIG. 7 illustrates experimental results obtained by applying a series offour stimuli of ascending amplitude on four adjacent electrodes to asheep spinal cord. Each stimulus was a tripolar stimulus for which therespective centre electrode was, in order, electrode E7, E8, E9 and E10,being the four centrally positioned electrodes of a 16 electrode linearelectrode array. Each stimulus was biphasic with each phase having apulse width of 20 μs, and the interphase gap being 10 μs. The stimuliwere of ascending amplitude, being 2 mA, 2.5 mA, 3 mA and 3.5 mArespectively. The inter-stimulus interval between each successive pairof stimuli on the respective electrodes was 33 μs, so that thepulse-to-pulse time was 83 μs, to optimally correlate the net evokedresponse in the antidromic (ie caudal) direction. As can be seen in FIG.7 the antidromic response 704 measured on electrode E16 was wellcorrelated from the four constituent parts, and is of large amplitude.In contrast, the four orthodromic responses were effectivelydecorrelated and produced a net response 702 measured at electrode E3which was of much reduced amplitude compared to response 704 travellingin the opposite direction, even though both were produced by the sameburst of four stimuli.

FIG. 8 shows the responses measured at different inter-stimulusintervals. As can be seen the inter-stimulus interval strongly affectsefficacy of this technique, and so preferred embodiments provide afeedback loop in order to optimize this parameter, and all otherstimulus parameters, in setting up the stimuli burst. FIG. 9 illustratesa suitable feedback controller for controlling the parameters of thestimuli burst in an automated manner, so as to use the measured evokedresponses in each direction to determine the stimulus parametersrequired to achieve a desired directional effect. Such automatedfeedback permits the relatively large parameter space to be efficientlyexplored to identify optimal stimuli burst parameters.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

1. A method of applying a neural stimulus with an implanted electrodearray, the method comprising: using the electrode array to applying asequence of stimuli configured to yield a therapeutic effect whilesuppressing psychophysical side effects, the stimuli sequence configuredsuch that a first stimulus recruits a portion of the fibre population,and a second stimulus is delivered within the refractory periodfollowing the first stimulus and the second stimulus being configured torecruit a further portion of the fibre population.
 2. The method ofclaim 1 wherein the sequence of neural stimuli comprises more than twostimuli, each being delivered in the refractory period following aprevious stimulus in the sequence.
 3. The method of claim 1 wherein thesequence of neural stimuli comprises stimuli of ascending amplitude. 4.The method of claim 1 wherein the sequence of neural stimuli is appliedsequentially by a single electrode.
 5. The method of claim 1 wherein thesequence of neural stimuli is applied sequentially by more than oneelectrode.
 6. The method of claim 5 wherein the second stimulus isdelivered at a time after the first stimulus which allows for cessationof the first stimulus and allows for propagation of a first neuralresponse evoked by the first stimulus from a first electrode to a secondelectrode, so that the second stimulus is delivered by the secondelectrode during a refractory period of neurons proximal to the secondelectrode after activation of those neurons by the evoked neuralresponse from the first stimulus.
 7. The method of claim 1 wherein thesequence of neural stimuli is applied by consecutive electrodespositioned along an electrode array.
 8. The method of claim 1 furthercomprising applying a stimulus which is not applied during therefractory period of any preceding stimulus, and which is not closelyfollowed by any subsequent stimulus in the refractory period of thesingle stimulus, in order to enable an evoked response measurement to bemade following the single stimulus.
 9. The method of claim 8 furthercomprising using the evoked response measurement for feedback control ofstimulus parameters of the sequence of neural stimuli.
 10. A device forapplying a neural stimulus, the device comprising: at least oneelectrode configured to be positioned alongside a neural pathway; and acontrol unit configured to apply a sequence of neural stimuli which areconfigured to yield a therapeutic effect while suppressingpsychophysical side effects, the stimuli sequence configured such that afirst stimulus recruits a portion of the fibre population, and a secondstimulus is delivered within the refractory period following the firststimulus and the second stimulus being configured to recruit a furtherportion of the fibre population.